The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor
Open accessAbstract
The stability and activity of hypoxia-inducible factor (HIF) are regulated by the post-translational hydroxylation of specific prolyl and asparaginyl residues. We show that the HIF asparaginyl hydroxylase, factor inhibiting HIF (FIH), also catalyzes hydroxylation of highly conserved asparaginyl residues within ankyrin repeat (AR) domains (ARDs) of endogenous Notch receptors. AR hydroxylation decreases the extent of ARD binding to FIH while not affecting signaling through the canonical Notch pathway. ARD proteins were found to efficiently compete with HIF for FIH-dependent hydroxylation. Crystallographic analyses of the hydroxylated Notch ARD (2.35A) and of Notch peptides bound to FIH (2.4-2.6A) reveal the stereochemistry of hydroxylation on the AR and imply that significant conformational changes are required in the ARD fold in order to enable hydroxylation at the FIH active site. We propose that ARD proteins function as natural inhibitors of FIH and that the hydroxylation status of these proteins provides another oxygen-dependent interface that modulates HIF signaling.
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“It also seems that increased NF-κB activity in hypoxia can be regulated by HIF-144, thus a cross-regulatory loop may exist between these two pathways and may involve other transcriptional regulators that bear non-redundant PHD sensitivity, including activating transcription factor-4 and Notch52,53”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [52]
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Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
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“Intriguingly, SUMO1 is itself hypoxia inducible, suggesting that sumoylation of HIFa, and other targets, modifies the response to hypoxia (Comerford et al., 2003; Lee et al., 2007).”
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“In addition, FIH, another important component of the oxygen-sensing pathway, was reported to negatively regulate the transcriptional activity of Notch, although this effect appeared to be independent of FIH catalytic activity (Coleman et al , 2007; Zheng et al , 2008).”
Metadata
- Authors
- Coleman, M. L., McDonough, M. A., Hewitson, K. S., Coles, C., Mecinovicí, J., Edelmann, M., Cook, K. M., Cockman, M. E., Lancaster, D. E., Kessler, B. M., Oldham, N. J., Ratcliffe, P. J., & Schofield, C. J.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Schofield, Christopher J.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 282
- Issue
- 33
- Pages
- 24027-24038
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2078263362
- Cited by
- 222
- References
- 34
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 10 · 2015: 13 · 2014: 14 · 2013: 19 · 2012: 11
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council (BBS/B/07683)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- FIH, Notch receptor, ankyrin repeat domain, hypoxia-inducible factor, protein stability, oxygen sensing, protein-protein interaction, conformational change, crystal structure, Notch signaling
- MeSH terms
- Receptor, Notch3, Asparagine, Humans, Mixed Function Oxygenases, Hydroxylation, Repressor Proteins, Transcription Factors, Ankyrin Repeat, Protein Structure, Tertiary, Crystallography, X-Ray, Hypoxia-Inducible Factor 1, alpha Subunit, Receptors, Notch, Receptor, Notch1, Receptor, Notch2
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